There are a number of pharmacological hypotheses about the mechanisms responsible for the differences in behavioral effects between standard and atypical DAT inhibitors and drugs considered to be atypical DAT inhibitors. As all drugs have multiple actions, the contribution of activity at off-target sites has to be considered. Other hypotheses that will be considered in more detail below are that kinetic differences between standard and atypical DAT inhibitors contribute to the differences in their effects, and that differences between the actions of standard and atypical DAT inhibitors mediated by the DA transporter contribute to differences in their effects. We reviewed the scientific literature that focuses on DAT ligands, such as benztropine, GBR 12909, modafinil, and DAT substrates derived from phenethylamine or cathinone that have atypical DAT-inhibitor effects, either in vitro or in vivo. The compounds are described from a molecular mechanistic, behavioral, and medicinalchemical perspective. Possible mechanisms for atypical effects at the molecular level could be deduced from the conformational cycle for substrate translocation. For each conformation, a crystal structure of a bacterial homolog was available, with a possible role of cholesterol, which is also present in the recently derived crystal structure of DAT from Drosophila. Although there is a direct relationship between behavioral potencies of most DAT inhibitors and their DAT affinities, a number of compounds bind to the DAT and inhibit dopamine uptake but do not share cocaine-like effects. Such atypical behavior, depending on the compound, may be related to slow DAT association, combined sigma-receptor actions, or bias for cytosol-facing DAT. Some structures are sterically small enough to serve as DAT substrates but large enough to also inhibit transport. Such compounds may display partial DA releasing effects, and may be combined with release or uptake inhibition at other monoamine transporters. Mechanisms of atypical DAT inhibitors may serve as targets for the development of treatments for stimulant abuse. These mechanisms are novel and their further exploration may produce compounds with unique therapeutic potential as treatments for stimulant abuse. Modafinil is clinically available for the treatment of sleep disorders. Because modafinil, like cocaine, targets the dopamine transporter, it is critical to determine its interactions with cocaine with regard to indicators of abuse liability. Modafinil (0.1-10 mg/kg iv) was not self-administered above vehicle levels in rats trained with cocaine, whereas in contrast methylphenidate self administration was maintained above vehicle levels. Both modafinil (10-32 mg/kg ip) and methylphenidate (1-10 mg/kg ip) pre-treatments dose-dependently potentiated the self administration of cocaine. The effects of cocaine on dopamine levels in the nucleus accumbens shell, a brain area involved in drug reinforcement, were enhanced whereas modafinil had no significant effects. The results suggest that modafinil may enhance reinforcing effects of cocaine though possibly through a mechanism that does not involve the dopamine transporter. Previous structure-activity studies indicated that a series of cocaine analogs (3-aryltropanes with various 2-diarylmethoxy substitutions) selectively bind the dopamine transporter (DAT) with nM affinity, and with corresponding 2&#945;-enantiomers having 10-fold lower affinity. We assessed the similarity to cocaine of behavioral effects of several of these compounds by examining effects on locomotion in mice and substitution for cocaine (10 mg/kg, ip) in rats discriminating cocaine from saline. Despite DAT affinity only the 2&#946;-Ph2COCH2-3-4-Cl-Ph analog fully substituted for cocaine's discriminative effects. Whereas all of the 2&#946; compounds increased locomotion, only the 2&#946;-(4-ClPh)PhCOCH2-3-4-Cl-Ph analog had cocaine-like efficacy. None of the 2&#945;-substituted compounds produced either of these cocaine-like effects. To explore the molecular mechanisms of these drugs, effects of the analogs on DAT conformation were assessed using a cysteine-accessibility assay. Previous results suggest that cocaine induces an outward-facing DAT conformation, whereas atypical DAT-inhibitors, such as benztropine, produce behavioral effects distinct from those of cocaine presumably by inducing an inward-facing conformation. Most of the 2&#946;- and 2&#945;-substituted compounds induced an outward-facing DAT conformation similar to that induced by cocaine. Consistent with a previous study of phenyltropane analogs, these behavioral and biochemical results show that phenyltropane analogs can bind to the DAT and induce outward-facing DAT conformations like cocaine and still produce effects that differ from those of cocaine. Modelling studies are being conducted to understand the molecular interaction of these unique compounds with the DAT. The mechanisms of amphetamine actions involve the dopamine transporter, however actions at the vesicular transporter are also involved. To study amphetamine function in dopamine neurons in vivo, we employed genetic and pharmacological tools in Drosophila melanogaster in behavioral and real-time optical experiments. Novel fluorescent reporters of vesicular cargo and of pH revealed that, at pharmacologically relevant concentrations, amphetamine must be transported both by the plasma membrane dopamine transporter and the vesicular monoamine transporter (VMAT) to cause vesicles to alkalize and redistribute their contents. We have newly acquired evidence that substrate-coupled H+ antiport provides the mechanism for amphetamine induced vesicular alkalization. The importance of VMAT for AMPH action was also demonstrated in rodents with a novel, selective VMAT inhibitor that blocked the behavioral effects of amphetamines but not cocaine, a competitive DAT inhibitor. Thus, both DAT and VMAT must work in tandem for amphetamine to produce its actions at pharmacologically relevant concentrations.